Percutaneous Coronary Intervention (PCI) is widely utilized to treat acute and stable coronary artery disease. Clopidogrel with aspirin is the most commonly prescribed anti-platelet drug used for PCI. Clopidogrel is a thienopyridine prodrug and requires the cytochrome P450 enzyme, CYP2C19, to convert it to its active thiol metabolite. Approximately 30% of Caucasians and 50% of Asians are carriers of genetic variants CYP2C19*2 and *3 that lead to loss of functional protein and hence these alleles are considered as loss of function (LOF) alleles. Due to an inability to adequately metabolize the drug, these patients have significantly reduced Clopidogrel active metabolite levels and high residual platelet reactivity with Clopidogrel therapy. As a result, the Food and Drug Administration (FDA) has issued a black box warning advising practitioners to consider alternative treatment in patients identified as CYP2C19 poor metabolizers who are to receive Clopidogrel and that these patients can be identified by genotyping. However, routine use of genotyping in patients who undergo PCI is not widely recommended or performed due to a lack of prospective clinical evidence that demonstrates patients with CYP2C19 LOF alleles would benefit from alternative anti-platelet therapy. To address this critical gap in clinical evidence, we propose performing a large, pragmatic, randomized trial (TAILOR-PCI), within existing PCI clinical practice settings, of genotyping compared with routine care to help determine whether identifying CYP2C19 LOF allele patients prospectively and prescribing alternative anti- platelet therapy such as ticagrelor in a randomized fashion would be clinically beneficial. 5,270 subjects will be enrolled to either prospective CYP2C19 genotyping or routine care. The primary analysis will be conducted only in the patients with CYP2C19*2 and *3 alleles (1,694 required for 80% power) who have either received Clopidogrel (control arm) or ticagrelor (genotype arm). The primary endpoints of the trial include myocardial infarction, stroke, cardiovascular (CV) death, severe recurrent ischemia, and stent thrombosis. Data collection will be obtained from routine clinical records and follow-up is by telephone. Data collection is based on the use of two established and long-standing registries: the American College of Cardiology's National Cardiovascular Data Registry CathPCI Registry and the Mayo Clinic PCI Registry. To achieve this goal we have created a network of 25 participating centers, all of which are actively recruiting, developed a study protocol and an electronic database, validated the point of care FDA-approved genotyping platform that will be used, and launched the initial phase of the vanguard study (n=1,963 subjects recruited). We propose completing the vanguard study (n=2,963 subjects) by April, 2016, and use the screening and recruitment strategies and collaborations developed in the vanguard phase to successfully implement the definitive trial (n=2,307 for a total of 5,270 subjects). This novel tril will attempt to answer one of the most important unresolved issues in interventional cardiology and has potential to change clinical practice in the cardiac catheterization laboratory.